Allopregnanolone for Traumatic Brain Injury

(ALLO Trial)

Overseen By Christine E Marx, MD MA

Age: 18 - 65

Sex: Any

Trial Phase: Phase 2

Sponsor: VA Office of Research and Development

Must not be taking: Prednisone, Benzodiazepines, Barbiturates, Opioids

Disqualifiers: Bipolar, Schizophrenia, Pregnancy, Seizures, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 4

Duration: 1 day

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether allopregnanolone (ALLO), a neurosteroid, can improve depression and pain in individuals with a history of mild traumatic brain injury (TBI). Participants will receive an infusion of either ALLO or a placebo to determine its effect on overall function. The trial is suitable for veterans who served in the U.S. military since 9/11, have experienced symptoms like confusion or brief loss of consciousness due to TBI, and are dealing with moderate depression and musculoskeletal pain. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Do I have to stop taking my current medications for the trial?

You may need to stop certain medications, like prednisone, that could affect the study results. However, you can continue taking medications for stable medical conditions, like hypertension, as long as they are well-controlled. Benzodiazepines, barbiturates, and opioids must not have been used in the last two weeks before joining the study.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research shows that allopregnanolone (ALLO) is under investigation for its safety in treating traumatic brain injuries. Previous studies suggest that ALLO is generally well-tolerated. In adult studies, it has aided recovery after brain injuries without major safety issues. Some research has examined ALLO's effects on the brain's structure and stress response, both crucial for healing.

Although detailed safety data is not yet available, research involving ALLO suggests it might be safe for humans. Current studies aim to confirm this and assess its effectiveness in alleviating depression and pain in individuals with mild traumatic brain injury. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for TBI?

Researchers are excited about allopregnanolone for traumatic brain injury because it introduces a novel approach by utilizing a neurosteroid that may help protect and repair brain cells. Unlike the standard treatments that often focus on reducing intracranial pressure or preventing seizures, allopregnanolone potentially enhances the brain's own repair mechanisms. This treatment works by modulating GABA receptors, which can help stabilize brain activity and promote recovery. Additionally, the infusion method allows for precise dosing, which could result in more consistent therapeutic effects. This unique mechanism and delivery have the potential to offer a new avenue for aiding recovery in traumatic brain injury patients.

What evidence suggests that allopregnanolone could be an effective treatment for mild traumatic brain injury?

Research has shown that allopregnanolone (ALLO) may alleviate symptoms related to traumatic brain injury (TBI). In this trial, participants will receive either a higher dose of ALLO (150 nM), a lower dose of ALLO (50 nM), or a placebo. Studies have found that ALLO can improve depression and pain in individuals with mild TBI. Early results suggest that ALLO might also enhance the ability to perform everyday activities. Additionally, research has explored ALLO's potential to treat symptoms after a concussion and post-traumatic stress disorder (PTSD), showing promise in these areas as well. These studies offer hope that ALLO could improve the quality of life for those affected by TBI. ^{1 3 5 6 7}

Who Is on the Research Team?

Christine E Marx, MD MA

Principal Investigator

Durham VA Medical Center, Durham, NC

Are You a Good Fit for This Trial?

This trial is for U.S. Military veterans aged 21-62 who have had a mild traumatic brain injury since 2001 and suffer from moderate depression (HAM-D score of at least 14) and musculoskeletal pain (BPI rating of at least 4). Participants must not be planning to change psychiatric medications or treatments during the study.

Inclusion Criteria

You have symptoms of psychosis, like seeing or hearing things that aren't there.

I experience confusion or disorientation.

My other health conditions are under control with medication.

Exclusion Criteria

I haven't used benzodiazepines, barbiturates, or opioids in the last 2 weeks.

I haven't been hospitalized for a serious illness in the last month and can manage my health conditions at home.

I am not pregnant or breast-feeding.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive an intravenous infusion of either ALLO or placebo, including a loading dose, 4-hour infusion, and taper

1 day

1 visit (in-person)

Post-Infusion Assessment

Behavioral assessments conducted during infusion, post-taper, and at 24 hours post-infusion

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness with behavioral assessments at 7 days and 14 days post-infusion

2 weeks

2 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Allopregnanolone
• Placebo

Trial Overview The trial tests whether allopregnanolone, given through an IV, can help with depression and pain in those with past mild TBI. It compares this treatment against a placebo. The main goal is to see if it improves mood and pain, with a secondary focus on overall function.

How Is the Trial Designed?

Group I: Placebo Experimental Treatment 1 Intervention

ALLO 0 nM (placebo: loading dose, 4-hour infusion, taper)

Group II: ALLO 50 nM Experimental Treatment 1 Intervention

ALLO 50 nM (lower dose ALLO: loading dose, 4 hour infusion, taper)

Group III: ALLO 150 nM Experimental Treatment 1 Intervention

ALLO 150 nM (higher dose ALLO: loading dose, 4 hour infusion, taper)

Allopregnanolone is already approved in United States for the following indications:

Approved in United States as Zulresso for:

• Postpartum depression

Who Is Running the Clinical Trial?

VA Office of Research and Development

Lead Sponsor

Trials

1,691

Recruited

3,759,000+

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT01673828

Allopregnanolone for the Treatment of Traumatic Brain Injury This study will provide initial data on the safety and effectiveness of allopregnanolone in improving neurobehavioral outcome and reducing mortality in adults

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10684848/

Neurosteroid Receptor Modulators for Treating Traumatic ... Recent evidence suggests that allopregnanolone may also be useful for post-concussive symptoms and post-traumatic stress disorder (PTSD) ...

3. apps.dtic.mil apps.dtic.mil/sti/tr/pdf/ADA614116.pdf

A Randomized Clinical Trial of Allopregnanolone for ... - DTIC This study will provide initial data on the safety and effectiveness of allopregnanolone in improving neurobehavioral outcome and reducing mortality in adults ...

4. thieme-connect.com thieme-connect.com/products/ejournals/pdf/10.1055/s-0040-1701323.pdf

The Role of Allopregnanolone Levels in Traumatic Brain Injury ... Results The levels of AP were significantly lower in the head trauma patients both in the adult and pediatric groups compared with the healthy ...

5. withpower.com withpower.com/trial/phase-3-brain-injuries-traumatic-2022-f9ebc

Allopregnanolone for Traumatic Brain Injury (ALLO Trial) This study will determine if allopregnanolone (ALLO) improves depression and pain symptoms in patients who have a history of mild traumatic brain injury ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9138587/

Current Clinical Trials in Traumatic Brain Injury - PMC Secondary outcomes of plasma norepinephrine levels showed higher levels after treatment: 48 patients enrolled. Results published. NCT01673828, Allopregnanolone ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S2352289522000777

Allopregnanolone: Regenerative therapeutic to restore ... According to McEwen and colleagues, a key outcome of stress in the brain is structural remodeling of neural architecture, which may be a sign of successful ...